US9861651B2 - Use of nicotinamide riboside to treat hearing loss - Google Patents

Use of nicotinamide riboside to treat hearing loss Download PDF

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US9861651B2
US9861651B2 US14/414,924 US201314414924A US9861651B2 US 9861651 B2 US9861651 B2 US 9861651B2 US 201314414924 A US201314414924 A US 201314414924A US 9861651 B2 US9861651 B2 US 9861651B2
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hearing loss
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nicotinamide riboside
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noise
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Kevin Brown
Anthony Sauve
Samie Jaffrey
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Cornell University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5058—Neurological cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • Noise exposure is a major cause of hearing loss worldwide. Following noise exposure, damage to diverse structures in the cochlea are seen, including the spiral ganglia nerve fibers that normally form synaptic contacts with hair cells in the cochlea. These synapses enable the spiral ganglia to convey acoustic information from the cochlea to higher order structures in the brain stem. Following noise exposure, hair cells release neurotransmitters that lead to excitotoxic damage in the neurites, resulting in synaptic disruption and neurite retraction (Kujawa, S. G. et al., J. Neuroscience, 29, 14077-14085 (2009); Lin, H. W.
  • the invention provides a method of preventing or treating hearing loss in a mammal in need thereof.
  • the method comprises administering to the mammal an effective amount of an agent that increases intracellular NAD+ in the mammal, thereby preventing or treating hearing loss in the mammal.
  • the invention also provides a method of determining if a compound acts as a neuroprotective agent.
  • the method comprises (a) providing a mammal, (b) administering an agent to the mammal, (c) exposing the mammal to noise, and (d) determining the level of NAD+ in hearing-related cells of the mammal, thereby determining if the compound acts as a neuroprotective agent based on the level of NAD+ in hearing-related cells of the mammal.
  • FIGS. 1A-1C depict representative NF-200 stains of untreated neurites (control), neurites treated with rotenone, and neurites treated with rotenone and NAD+, respectively.
  • FIG. 2 is a graphical representation of the percentage of beading neurites in untreated neurites (control), neurites treated with rotenone, and neurites treated with rotenone and NAD+.
  • FIGS. 3A-3C depict threshold shifts in noise-exposed WldS mice and wild-type mice that were measured using 8000 Hz, 16,000 Hz and 32,000 Hz tone bursts, respectively.
  • FIGS. 4A-4C depict hearing loss in C57BL6 mice that were either untreated control mice or mice treated with nicotinamide riboside before, after, and both before and after exposure to 8000 Hz, 16,000 Hz and 32,000 Hz tone bursts, respectively.
  • FIG. 5 is a diagrammatic representation of the spatial relation of spiral ganglia neurites to the base of inner hair cells.
  • FIG. 6 is a graphical comparison of the distance between spiral ganglia neurites and inner hair cells between noise-exposed mice that were either vehicle-treated control mice or nicotinamide riboside-treated mice at 24 h and 2 weeks after exposure.
  • the invention provides a method of preventing or treating hearing loss in a mammal in need thereof.
  • the method comprises administering to the mammal an effective amount of an agent that increases intracellular NAD+ in the mammal, thereby preventing or treating hearing loss in the mammal.
  • the agent that increases intracellular NAD+ can be any suitable agent that increases intracellular NAD+.
  • the agent is nicotinamide riboside.
  • the hearing loss can be caused by a variety of circumstances.
  • the hearing loss can be caused by noise exposure.
  • the agent can be administered to the mammal before, during, and/or after noise exposure.
  • the hearing loss can be caused by drug toxicity.
  • the drug toxicity results from treatment of the mammal with gentamicin or cisplatin.
  • the agent can be administered before, during, and/or after exposure to the toxic drugs.
  • the hearing loss can be associated with Meniere's disease.
  • Meniere's disease is a disorder of the inner ear that can affect hearing and balance to a varying degree. It is characterized by episodes of vertigo, low-pitched tinnitus, and hearing loss.
  • the hearing loss associated with Meniere's disease has been suggested to involve excitotoxic damage to spiral ganglia neurons.
  • Hearing implants such as cochlear implants endeavor to preserve native hearing while placing a implantable device in the ear. This hearing preservation may be accentuated by applications of the agent increases intracellular NAD+.
  • Comorbid conditions with hearing loss including vertigo (dizziness), tinnitus (ringing in ear) and hyperacusis (sensitivity to loud noises) may also be effectively treated by the agent increases intracellular NAD+.
  • the agent increases intracellular NAD+ in one or more cells selected from the group consisting of spiral ganglia nerve cells, hair cells, supporting cells, and Schwann cells.
  • the agent suppresses oxidative damage in the cell.
  • the agent activates SIRT3.
  • Endogenous SIRT3 is a soluble protein located in the mitochondrial matrix. Overexpression of SIRT3 in cultured cells increases respiration and decreases the production of reactive oxygen species. Without wishing to be bound by any particular theory, it is believed that activation of SIRT3 is implicated in suppression of oxidative damage in the aforesaid cells.
  • the treating of the mammal with the agent results in prevention of hearing loss. In other embodiments, the treating of the mammal with the agent results in the mitigation of hearing loss.
  • the agent that increases intracellular NAD+ can be administered using any suitable method.
  • the agent that increases intracellular NAD+ can be administered orally, by injection, or by intratympanic injection into the middle ear space.
  • an effective amount of the agent that increases intracellular NAD+ can be an amount effective to inhibit, attenuate, or reverse hearing loss symptoms.
  • the specific effective amount may vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), the specific formulations employed, and the structure of the agent.
  • the doses of the agent administered to a mammal, particularly, a human, in accordance with the invention should be sufficient to effect the desired response. Such responses include reversal or prevention, in whole or in part, of the hearing loss.
  • the agent dosage and administration regimen will depend upon a variety of factors, including the age, condition, and body weight of the mammal, as well as the particular type of the cause of hearing loss and extent of the hearing loss in the mammal.
  • the size of the doses will also be determined by the routes, timing, and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of the agent that increases intracellular NAD+ and the desired physiological effect.
  • the treatment of hearing loss may require prolonged treatment involving multiple administrations of the agent to the mammal.
  • Suitable agent doses and administration regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the agent that increases intracellular NAD+. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the inventive method typically will involve the administration of about 0.1 to about 300 mg of the agent that increases intracellular NAD+ described above per kg body weight of the mammal.
  • the agent that increases intracellular NAD+ can be administered to the mammal by itself or in the form of a pharmaceutical composition comprising the agent and a pharmaceutically acceptable carrier.
  • the agent that increases intracellular NAD+ can be administered in a pharmaceutical composition, i.e., in admixture with one or more suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • a pharmaceutically acceptable carrier suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the pharmaceutical composition can be in any suitable form, for example, in a form suitable for oral, direct injection, or intratympanic administration.
  • the carrier can be a solid or liquid, and the type of carrier is generally chosen based on the contemplated route of administration.
  • the agent that increases intracellular NAD+ can be co-administered along with the pharmaceutically acceptable carrier in the form of a tablet or capsule, liposome, as an agglomerated powder, or in a liquid form.
  • suitable solid carriers include lactose, sucrose, gelatin and agar.
  • Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • suitable liquid dosage forms include (a) solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents (including esters), (b) emulsions, (c) syrups, (d) elixirs, (e) tinctures, suspensions, (f) suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Oral dosage forms optionally contain flavorants and coloring agents.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the comtemplated route of administration, for example, by bolus or infusion.
  • Injectable forms may include, for example, intraperitoneal, subcutaneous, or intramuscular forms.
  • the agent that increases intracellular NAD+ can be administered in the form of a nutraceutical, that is, in admixture with foodstuffs or beverages.
  • the pharmaceutical composition may include the agent that increases intracellular NAD+ may include other compounds also used to treat neurite damage.
  • the invention also provides a method of determining if a compound acts as a hearing protective agent.
  • the method comprises (a) providing a mammal, (b) administering an agent to the mammal, (c) exposing the mammal to noise, and (d) determining the level of NAD+ in hearing-related cells of the mammal, thereby determining if the compound acts as a hearing protective agent based on the level of NAD+ in hearing-related cells of the mammal.
  • a compound will be useful as a hearing protective agent.
  • hearing loss is a sirtuin and NAD+-sensitive pathway and that nicotinamide riboside protects against and treats hearing loss, especially noise-induced hearing loss.
  • a determination can be made as to whether a compound can prevent and/or treat hearing loss by evaluating whether the compound acts in neurons by using noise-induced hearing loss paradigms. If the compound is able to increase NAD+ in hearing-related cells, then that compounds will exhibit protection from, and be able to treat hearing loss, especially noise-induced hearing loss.
  • HBSS ⁇ / ⁇ Hanks Balanced Salt Solution
  • DMEM Dulbecco's Modified Eagle Medium
  • PBS phosphate buffered saline
  • BSA bovine serum albumin
  • DAPI 4′,6-diamidino-2-phenylindole.
  • Nicotinamide riboside was synthesized as previously described in Yang, T. et al., J. Med. Chem. 50, 6458-6461 (2007). Other chemicals and reagents were purchased from Sigma except as otherwise indicated below.
  • mice Male and female C57/BL6J mice were purchased from Jackson Laboratories. WldS +/+ mice were a kind gift of Dr. Michael Coleman (Babraham Institute, University of Cambridge).
  • Dissociated spiral ganglia neurons were harvested from P5 rats. Briefly, pups were rapidly decapitated, and cochlea were dissected. The modiolus was then dissected and digested (0.1% trypsin, 0.1% collagenase, HBSS ⁇ / ⁇ ) for 45 min at 37° C. Sequential trituration was performed with fire-polished pipets to release cells from the tissue, and cells were transferred to laminin/polylysine-coated 24-well plates. Neurons were incubated overnight in culture media (DMEM high glucose, N2 supplement, 10 ⁇ g/ml insulin, 25 ⁇ g/ml BDNF, 25 ⁇ g/ml NT3). To elicit neurite degeneration, cultures were incubated with rotenone (10 ⁇ M) for 2 hr in the presence/absence of 10 mM NAD+.
  • DMEM high glucose, N2 supplement, 10 ⁇ g/ml insulin, 25 ⁇ g/ml BDNF, 25
  • Spiral ganglia neuron cultures were fixed with 4% paraformaldehyde and permeabilized with 0.5% Triton X-100TM/PBS for 10 min. After washing, cells were blocked with 4% donkey serum and incubated with mouse anti-NF200 (1:1000) overnight at 4° C. Neurite beading was then measured using a previously described, unbiased computerized protocol (Sasaki, Y. et al., J. Neuroscience, 29, 5525-5535 (2009)).
  • Mouse cochlea were prepared as described in Whitlon, D. S. et al., Brain Research Protocols, 6, 159-166 (2001). Mouse cochlea were quickly dissected from the temporal bone following rapid decapitation. Once separated, the apex of the cochlea was gently fenestrated, and the cochlea were immediately fixed in 4% paraformaldehyde overnight at 4° C. The cochlea were then washed with three changes of PBS and incubated in a decalcification solution (10% EDTA/PBS pH 7.4) under constant rotation at 4° C. for 1 week. The decalcification solution was changed daily.
  • a decalcification solution (10% EDTA/PBS pH 7.4
  • Cochlea were washed in 3 changes of PBS and then treated with progressively increasing sucrose concentrations from 10-30%. The cochlea were incubated overnight in 30% sucrose at 4° C. The cochlea were incubated an additional 24 hr in OCT compound (Tissue-Tek). Following the final incubation, the cochlea were transferred to cryomolds, carefully aligning the modiolus parallel to the bottom of the mold, and frozen over dry ice. Mid-modiolar samples were then cut at a 10 ⁇ m thickness and mounted on glass slides (VWR SUPERFROSTTM Plus). Sections were then dried for 2 hr prior to staining.
  • Auditory brainstem response testing was performed as previously described (Willott, J. F., Current Protocols in Neuroscience, 8.21B, B1-B12 (2005). Animals were tested following sedation with ketamine and xylazine (40 mg/kg and 10 mg/kg, respectively). Tone burst stimuli at 8, 16, and 32 kHz for 0.5 msec were used to elicit auditory evoked responses using an auditory brainstem recording system (Intelligent Hearing Systems, Miami, Fla.). An evoked response was determined by identifying waveforms at proper time intervals that increased in magnitude with increasing volume as described previously by Willott.
  • mice were exposed to a 90 dB octave band for 2 hr in a cage placed in a soundproof chamber (MAC-2, Industrial Acoustics Company, Bronx N.Y.). The mice were able to freely move throughout the cage.
  • the octave band was generated using ToneGen software (NCH software, Greenwood Village, Colo.) routed through an Audiosource Amp100 amplifier driving two down-facing Fostex FT-96H speakers.
  • the sound pressure level was confirmed at 0, 30, 60, and 90 min, and again just prior to completion of sound exposure using an Extech microphone 407736.
  • Axonal degeneration in a variety of neurons can be blocked by treatment with millimolar concentrations of NAD+ (Avery, M. A., et al., Current Biology, CB 22, 596-600 (2012)).
  • NAD+ millimolar concentrations of NAD+
  • rotenone which is a mitochondrial complex I inhibitor that has previously been shown to induce axonal degeneration in axons of dorsal root ganglia neurons
  • the Wallerian degeneration slow (WldS) mouse expresses a triplicate repeat of a gene fusion of the NAD biosynthetic enzyme Nicotinamide mononucleotide adenylyl transferase 1 and Ube4a (Coleman, M. P, et al., Proc. Natl. Acad. Sci. USA, 95, 9985-9990 (1998)). WldS is highly expressed in neurons, and its expression markedly delays degeneration of the distal axonal fragment following axonal transaction (Araki, T. et al., Science, 305, 1010-1013 (2004)).
  • WldS expression also mitigates disease phenotypes of mice that are susceptible to various neurodegenerative diseases (Samsam, M., et al., J. Neuroscience, 23, 2833-2839 (2003); Kaneko, S. et al., J. Neuroscience, 26, 9794-9804 (2006); Sajadi, A. et al., Current Biology , CB 14, 326-330 (2004)).
  • WldS acts in axons to maintain axonal NAD biosynthesis after axonal injuries (Wang, J, et al., J. Cell Biol. 170, 349-355 (2005)), which typically results in the loss of endogenous NAD biosynthetic enzymes (Gilley, J. et al., PLoS Biology, 8, e1000300 (2010)).
  • the WldS mouse provides a genetic test of whether augmented NAD biosynthesis can be used to interfere with axonal degeneration processes.
  • ABR auditory brainstem responses
  • TTS Transient threshold shifts
  • PTS permanent threshold shifts
  • threshold shifts in noise-exposed WldS mice were measured using 8000 Hz, 16,000 Hz and 32,000 Hz tone bursts.
  • the transient threshold shift at 32,000 Hz was 38 dB ( FIG. 3C ).
  • a threshold shift of 21 dB was observed ( FIG. 3B ).
  • a smaller shift of 10 dB was noted at 8000 Hz ( FIG. 3A ).
  • These threshold shifts persisted at 14 days. The persistence of these threshold shifts indicates that the mice have permanent hearing loss. The more prominent hearing loss at higher frequencies following noise exposure is consistent with previous findings (Wang, Y. et al., Journal of the Association for Research in Otolaryngology, 3, 248-268 (2002)).
  • mice In contrast, the WldS mice exhibited pronounced protection from noise-induced hearing loss. At 24 hours following acoustic trauma, mice exhibited no threshold shift at 8000 and 16,000 Hz, and a mild 10 dB threshold shift at 32,000 Hz ( FIGS. 3A-3C ). By 14 days, no threshold shift was seen at any frequency. Taken together, these data show that WldS animals exhibit marked resistance to both transient and permanent losses of hearing following acoustic trauma.
  • Nicotinamide riboside is a well-tolerated precursor of NAD+.
  • NR was administered by intraperitoneal injection twice daily at 1000 mg/kg, a dose which increases tissue NAD levels by 50%, either for 5 days prior to noise exposure and 14 days after noise exposure (NR Before+ After), 5 days prior to noise exposure (NR Before), or 14 days after noise exposure (NR After).
  • NR-treated mice exhibited negligible transient threshold shifts at 24 hours at 8000 Hz and 16,000 Hz (6 and 8 dB respectively), and a reduced threshold shift at 32,000 Hz (16 dB).
  • the hearing loss at 8000 Hz, 6,000 Hz, and 32,000 Hz is set forth in the Table and is depicted graphically in FIGS. 4A-4C , respectively. Mice were similarly protected from permanent hearing loss at all 3 frequencies. These data indicate that NR treatment markedly reduces noise-induced hearing loss.
  • This example demonstrates the effect of nicotinamide riboside on retraction of spiral ganglia neurites from the inner hair cells.
  • Noise-induced hearing loss is associated with retraction of spiral ganglia neurites from the inner hair cells. As the most prominent hearing losses are seen in the portion of the auditory spectrum that contains the highest audible frequencies, the basal turn of the cochlea where this portion of the auditory spectrum is detected was focused on. In this part of the cochlea, noise-induced cellular damage is greatest. Immunofluorescence labeling of the cochlea can readily show whether spiral ganglia neurites are forming their proper contacts with the base of inner hair cells. The base of the inner hair cells is demarcated by the location of the nucleus in these cells, since it rests on the base of the cell.
  • spiral ganglia neurites are seen adjacent to the base of the inner hair cells.
  • the spiral ganglia neurites were refracted from inner hair cells by 29.5 ⁇ 12.9 ⁇ m 24 hr following noise exposure.
  • the neurites remained retracted (23 ⁇ 3.6 ⁇ m) 14 d after noise exposure.
  • the persistent retraction indicates a permanent loss of synaptic connectivity between hair cells and spiral ganglia neurites in vehicle-treated animals after noise exposure.

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